N-acetyl-neuraminidase is a lysosomal enzyme deficient in the inherited lysosomal storage disorders, sialidosis and galactosialidosis. Both diseases are clinically heterogeneous exhibiting both mild and severe forms. The former disease is thought to arise from mutations in the structural gene coding for neuraminidase. The latter disease results from a defect in a glycoprotein called protective protein which appears essential for maintenance of activity of both neuraminidase and beta- galactosidase. All three proteins copurify and are believed to exist as a functional complex within the lysosome. Three approaches are being followed to clone the mammalian neuraminidase. (1) The complex has been purified from bovine testicular tissue for use in isolation of neuraminidase to obtain amino acid sequence information for cloning purposes. (2) A set of degenerate primers based on a five amino acid sequence motif found in viral, bacterial and trypanosome neuraminidases has been used to PCR amplify MRNA form human fibroblasts in attempts to capture an authentic CDNA fragment coding for neuraminidase. (3) An 80,000 bp segment of DNA located on chromosome 6 in the class III gene region of the major histocompatibility complex believed to contain the gene for neuraminidase has been isolated and we are attempting to trap the neuraminidase exons for use in screening a CDNA library. This approach is based on the following; a) a study that describes a single patient exhibiting the clinical features of both sialidosis and congenital adrenal hyperplasia along with the corresponding enzyme deficiencies of neuraminidase and 21 hydroxylase thereby suggesting a location for the neuraminidase gene proximal to that of the 21 hydroxylase gene on chromosome 6 in the class III gene region of the major histocompatibility complex and b) a suggestion of the presence of the sequence motif found in viral, bacterial and trypanosome neuraminidase in a newly discovered cluster of genes neighboring the 21 hydroxylase gene.